Over the last decade, surveys in European and US hospitals have shown that more than 60% of patients in pediatric wards receive one or more prescriptions unlicensed or off-label for children. Despite important progress, several drugs are still unavailable in oral formulations suitable for infants and children. Our preliminary experiments show that the casein micelles from bovine milk can be modified to (1) bind low molecular weight (MW) hydrophobic molecules, and (2) dried to a milk-based powder and re-suspended in an aqueous phase to permanently disperse hydrophobic molecules. The objective of this proposal is to use modified casein micelles from bovine milk as carrier systems for the delivery of the low MW hydrophobic ritonavir (MW = 721 KDa, Log P > 3.9) into the small intestine. The central hypothesis is that the casein micelle can be modified to facilitate the intestinal absorption of hydrophobic molecules. This hypothesis is formulated based on exploratory experiments showing that (1) modified casein micelles strongly bind the hydrophobic molecule triclosan, (2) little triclosan is released in the 3-5 pH range and, (3) release is favored at pH e 7. Both in vitro and in vivo experiments are needed to determine the key physicochemical mechanisms that promote load, the release kinetics of loaded micelles, and the effect of gastric enzymes on casein-drug systems. In order to achieve this objective we have assemble a multidisciplinary team that has the required breadth and scope of experience. We plan to test our central hypothesis by pursuing the following four specific aims: Specific aim 1: Optimize the physicochemical conditions that maximize casein micelle association to specific ritonavir polymorphs.; Specific aim 2: Determine the release kinetics of ritonavir in vitro model systems simulating stomach and small intestine; Specific aim 3: Determine bioavailability following casein-ritonavir administration in a young pig model, and compare it to the commercially available formulation (i.e., Norvir). The rationale for the proposed research is that by capitalizing on the casein micelle's carrying capabilities, we will be able to develop milk-based ethanol-free powder systems to disperse hydrophobic drugs and improve bioavailability of oral formulations targeting infant and child populations.